The compound tiotropium bromide (1) whose molecular structure is depicted below is known from the European Patent Application EP0418716.

Tiotropium bromide is a highly effective active pharmaceutical ingredient which is administrated in low (microgram) therapeutic doses by inhalation. Highly effective pharmaceutical, active substances used for preparing pharmaceutical compositions suitable for administration by inhalation have to be of high chemical purity and have to be of high polymorphic purity. Crystalline polymorphic forms of tiotropium bromide have been reported in various publications (U.S. Pat. No. 6,777,423; EP14101445; EP16825442; EP1879888; EP2085396; EP1869035; and WO2011/015882) showing that the compound may give rise to a variety of solids having distinct physical properties. This invention discloses a process for the preparation of tiotropium bromide which consistently affords product with outstanding chemical purity and which affords a single, pure polymorph with a consistent level of polymorphic purity.
The preparation of tiotropium bromide was first disclosed in EP0418716 and the synthesis described in this patent involves the transesterification reaction between scopine (ii) and MDTG (III), to prepare N-demethyltiotropium (IV), followed by reaction of N-demethyltiotropium with bromomethane to prepare tiotropium bromide (Scheme 1).

One disadvantage of this route is the use of scopine as a starting material because scopine is a sensitive compound that tends to liquefy when exposed to air and, due to its inherent instability, it is not commercially available. Another disadvantage is the use of hazardous reagents, such as sodium metal, in the transesterification reaction to form N-demethyltiotropium. The yields reported for the preparation of N-demethyltiotropium vary between 45% and 70% (of theoretical) but the highest yield is obtained when the transesterification reaction is carried out in a melted mixture of scopine and MDTG, what is a cumbersome procedure to employ in an industrial process.
U.S. Pat. No. 6,486,321 describes an alternative process for the preparation of tiotropium bromide which starts from tropenol (V) hydrochloride. However, this process is more complex than the process disclosed in EP0418716 because it encompasses a longer synthetic route than that of EP0418716 (Scheme 2).

U.S. Pat. No. 6,747,154 describes a short route of synthesis to prepare tiotropium bromide where this product is prepared by a direct coupling reaction between MTDG and scopine methyl bromide (VII) in the presence of a coupling agent such as carbonildiimidazolide and of bases such as alkali metal imidozolides (Scheme 3). However, details on the purity of the products obtained according to the process claimed are not disclosed. In addition to the absence of details on the purity, the product obtained by following the claimed process is purified and the yield reported for the purification is low, 74% (w/w). In spite of following a short synthetic route, the process requires the use of hazardous reagents such as alkali metals or alkali hydride metals (such as lithium hydride) to prepare the metal salts of the bases. Another disadvantage of this process is that the coupling agents employed (carbonyldiimidazole, or carbonyldi-1,2,4-triazole or dicyclohexylcarbodiimide) are expensive reagents.

U.S. Pat. No. 7,662,963 describes the preparation of N-demethyltiotropium by reaction of a scopine salt of formula (IX) with MDTG, in the presence of a weak inorganic base, and in a polar organic solvent (Scheme 4). The salts of scopine disclosed are the bromide (X is Br−), the chloride (X is Cl−), the sulfate (X is SO42−), the acetate (X is CH3COO−), the phosphate (X is PO42−), the methane sulfonate (X is CH3SO3−), the tartarate, the fumarate, the citrate, the maleate, the succinate, the p-toluene sulphonate and the amido sulphonate. However, the purities (by HPLC) reported in examples for the preparation of N-demethyltiotropium process are of 70% (example 12), 98.3% (examples 11 and 21) and 98.5% (example 13). In comparison, the purity of N-demethyltiotropium obtained according to the process of the present invention is greater than 99.0%.

WO2009087419 describes a process to prepare N-demethyltiotropium (which is designated as tiotropium base) and tiotropium bromide with a purity greater than 95%, by HPLC, said process comprising the transesterification of scopine, or a salt thereof such as scopine hydrochloride, with MDTG in the presence of an organic amine base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and a further base such as an inorganic base. An inorganic base such as sodium hydride (NaH) is used to liberate scopine from the corresponding hydrochloride salt. Although the application states that the use of DBU is very advantageous because it allows N-demethyltiotropim to be prepared with a purity of preferably greater than 99% by HPLC, no details are disclosed in the description of the process explaining how such a high purity can be achieved. In addition, the sole example reporting the purity of N-demethyltiotropium presents a purity of 98% by HPLC. To obtain N-demethyltiotropium with purity higher than 98% the material obtained according to the claimed process is recrystallized from acetonitrile and the yield reported is only 86% (w/w); the purity reported for the crystallized product is 99.8% by HPLC. In the example describing an alternative process to prepare tiotropium bromide, which is a telescoped process where the intermediate N-demethyltiotropium bromide is not isolated and is used in solution for the reaction with methyl bromide, the purity reported for the tiotropium bromide obtained is 98.66%. The examples presented also show that, tiotropium bromide 99.83% pure by HPLC is obtained from crystallized N-demethyltiotropium (material with a purity greater than 99.8% by HPLC) whilst tiotropium bromide with a purity of only 98.66% by HPLC is obtained from N-demethyltiotropium that is not crystallized.
WO2011/015884 describes a process to prepare N-demethyltiotropium and tiotropium bromide in substantially pure form, which process comprises the transesterificaiion of scopine, or a salt thereof, with MDTG, wherein the transesterification reaction is performed in the presence of an organic base such as DBU and an inorganic base such as potassium carbonate. The application states that N-demethyltiotropium and the tiotropium bromide obtained by the process claimed have a purity of at least 99% by HPLC. The example presented for the preparation of N-demethyltiotropium refers to a product with a purity of 98.7% and the example for the preparation of tiotropium bromide refers to a product with a purity of 99.9%. One disadvantage of this process is that two bases are required to obtain N-demethyltiotropium with purity of 99% by HPLC. The other disadvantage is that the organic bases claimed (triethylamine, diisopropylethylamine, DBU, DBN, DMAP) are very expensive when compared to potassium carbonate and, the amount of organic base used is significant (3 eq.). Surprisingly, the present invention shows that N-demethyltiotropium cap be prepared with purity greater than, 99.0%, by HPLC using only potassium carbonate, a cheap base which can be easily eliminated from the process as shown below. It also shows that tiotropium bromide with purity equal to, or greater than, 99.5% by HPLC can be prepared by following the process of the present invention.
According to a first aspect of the present invention, there is provided a process for preparing N-demethyltiotropium with purity greater than 99.0% by HPLC. In this process, scopine oxalate is, treated with diethylamine to afford scopine, and the scopine so formed is combined with MDTG in the presence of anhydrous potassium carbonate to form N-demethyltiotropium. Surprisingly, it has been found that N-demethyltiotropium can be obtained in very high purity when prepared according to the process of the present invention. Since the purity of this compound is very high, it can be used in the synthesis of tiotropium bromide without further purification and allows tiotropium bromide with purity greater than 99.5% to be prepared. By avoiding a purification step this approach a great benefit in a commercial process as it saves significant amounts of time and costs. In a second aspect, the present invention provides a process for manufacturing tiotropium bromide with a high purity, equal to, or greater than 99.5%.
WO2007/0225314 describes three different crystalline forms of tiotropium bromide which may be prepared by crystallizing the product from methanol and acetone. According to the application, Form 1 can be obtained by crystallizing the product from a mixture of methanol and acetone with a ratio of 1/1 (vol./vol.), Form 2 can be obtained by crystallization from a mixture of methanol and acetone with a ratio ranging from 1/1 (vol./vol.) to ⅓, and Form 3 can be obtained by crystallization from a mixture of methanol and acetone with a ratio of 3/1 (vol./vol.).
Surprisingly, it has been found that the process of this invention affords tiotropium bromide in a single and pure crystalline form. The process of the present invention encompasses a crystallization of tiotropium bromide from mixtures of methanol and acetone with different proportions, wherein a single crystalline form is obtained regardless of the proportion of methanol and acetone employed in the crystallization. When carrying out the crystallization of tiotropium bromide in mixtures of methanol and acetone with a methanol proportion higher than acetone e.g. methanol and acetone 3/1 (vol./vol.), or a proportion of acetone higher than methanol e.g. pethanol and acetone ⅓ (vol./vol.) or even with the same proportion of methanol and acetone, the process of this invention consistently affords a single and pure anhydrous crystalline form. Hence, in a third aspect, the present invention provides a process to consistently obtain a single pure anhydrous crystalline form of tiotropium bromide.
Finally, a fourth aspect of the present invention is the development of a suitable micronization method to obtain tiotropium bromide with adequate particle size for inhalation while maintaining its polymorphic form.
Jet milling is the most often employed process for the micronization of inhalation products. US2010/0215590 describes a process for the production of virtually anhydrous micronized tiotropium bromide comprising the use of monohydrate tiotropium monohydrate as raw material. The process described is conducted using a gas jet mill which is known as a high energy size reduction process that breaks down active substance crystals, impacting surface energy and crystal form. The output material often contains significant amounts of amorphous material, which can influence both the stability of the finished product and the formulation. Surprisingly, the current invention uses a milling process that maintains the polymorphic form of tiotroprium bromide and allows controlling the particle size.